Optimisation of anti-interleukin-6 therapy: Precision medicine through mathematical modelling.

Background: Dysregulated interleukin (IL)-6 production can be characterised by the levels present, the kinetics of its rise and its inappropriate location. Rapid, excessive IL-6 production can exacerbate tissue damage in vital organs. In this situation, therapy with an anti-IL-6 or anti-IL-6 receptor (IL-6R) monoclonal antibody, if inappropriately dosed, may be insufficient to fully block IL-6 signalling and normalise the immune response. Methods: We analysed inhibition of C-reactive protein (CRP) - a biomarker for IL-6 activity - in patients with COVID-19 or idiopathic multicentric Castleman disease (iMCD) treated with tocilizumab (anti-IL-6R) or siltuximab (anti-IL-6), respectively. We used mathematical modelling to analyse how to optimise anti-IL-6 or anti-IL-6R blockade for the high levels of IL-6 observed in these diseases. Results: IL-6 signalling was insufficiently inhibited in patients with COVID-19 or iMCD treated with standard doses of anti-IL-6 therapy. Patients whose disease worsened throughout therapy had only partial inhibition of CRP production. Our model demonstrated that, in a scenario representative of iMCD with persistent high IL-6 production not controlled by a single dose of anti-IL-6 therapy, repeated administration more effectively inhibited IL-6 activity. In a situation with rapid, high, dysregulated IL-6 production, such as severe COVID-19 or a cytokine storm, repeated daily administration of an anti-IL-6/anti-IL-6R agent, or alternating daily doses of anti-IL-6 and anti-IL-6R therapies, could neutralise IL-6 activity. Conclusion: In clinical practice, IL-6 inhibition should be individualised based on pathophysiology to achieve full blockade of CRP production. Funding: EUSA Pharma funded medical writing assistance and provided access to the phase II clinical data of siltuximab for analysis.

Perfluorodioxolane Polymers for Gas Separation Membrane Applications.

Since the discovery of polytetrafluoroethylene (PTFE) in 1938, fluorinated polymers have drawn attention in the chemical and pharmaceutical field, as well as in optical and microelectronics applications. The reasons for this attention are their high thermal and oxidative stability, excellent chemical resistance, superior electrical insulating ability, and optical transmission properties. Despite their unprecedented combination of desirable attributes, PTFE and copolymers of tetrafluoroethylene (TFE) with hexafluoropropylene and perfluoropropylvinylether are crystalline and exhibit poor solubility in solvents, which makes their processability very challenging. Since the 1980s, several classes of solvent-soluble amorphous perfluorinated polymers showing even better optical and gas transport properties were developed and commercialized. Amorphous perfluoropolymers exhibit, however, moderate selectivity in gas and liquid separations. Recently, we have synthesized various new perfluorodioxolane polymers which are amorphous, soluble, chemically and thermally stable, while exhibiting much enhanced selectivity. In this article, we review state-of-the-art and recent progress in these perfluorodioxolane polymers for gas separation membrane applications.

Optimization of the Electrodeposition of Gold Nanoparticles for the Application of Highly Sensitive, Label-Free Biosensor.

A highly sensitive electrochemical biosensor with a signal amplification platform of electrodeposited gold nanoparticle (AuNP) has been developed and characterized. The sizes of the synthesized AuNP were found to be critical for the performance of biosensor in which the sizes were dependent on HAuCl4 and acid concentrations; as well as on scan cycles and scan rates in the gold electro-reduction step. Systematic investigations of the adsorption of proteins with different sizes from aqueous electrolyte solution onto the electrodeposited AuNP surface were performed with a potentiometric method and calibrated by design of experiment (DOE). The resulting amperometric glucose biosensors was demonstrated to have a low detection limit (> 50M) and a wide linear range after optimization with AuNP electrodeposition.

Effects of Chain-Chain Associations on Hybridization in DNA Brushes.

Hybridization of solution nucleic acids to DNA brushes is widely encountered in diagnostic and materials science applications. Typically, brush chain lengths of ten or more nucleotides are used to provide the needed sequence specificity and binding affinity. At these lengths, coincidental occurrence of complementary regions is expected to lead to associations between the nominally single-stranded brush chains due to intra- or interchain base pairing. This report investigates how these associations impact the brushes' hybridization activity toward complementary "target" sequences. Brushes were prepared from 20-mer chains with four-nucleotide-long "adhesive regions" through which neighboring chains could interact. The affinity and position of the adhesive region along the chain backbone were varied. DNA brushes were exposed to complementary solution targets, and the corresponding melting transitions were measured to estimate free energies of the brush-target hybridization. These results revealed that higher affinity adhesive regions more extensively suppressed brush hybridization relative to hybridization in solution. Associations near the middle of the chains were found to be more penalizing than those at the immobilized or the free end of the chains. Provided that the brush chains were close enough to associate, changes in brush density did not exert a significant effect on hybridization thermodynamics within the investigated coverage window. Comparison of the DNA brush results with those from commercial Affymetrix single-nucleotide-polymorphism (SNP) microarrays revealed agreement in the impact of chain associations on hybridization.

Surface vs. solution hybridization: effects of salt, temperature, and probe type.

Hybridization thermodynamics on solid supports are compared with those in solution for two types of hybridization probe, DNA and uncharged morpholino oligonucleotides of identical sequences. Trends in hybridization affinity are discussed with respect to ionic strength, temperature, and surface behavior.